Biochem J 2002 May 7;Pt [epub ahead of print]
Sharpe MA, Ollosson R, Stewart VC, Clark JB.
Manganese salen complexes (Mn-Salen), including EUK-8 and EUK-134, have been reported to possess combined superoxide dismutase (SOD) and catalase mimetic functions.
Because of this SOD/catalase mimicry, EUK-8 and EUK-134 have been investigated as possible therapeutic agents in neurological disorders resulting from oxidative stress, including Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis.
These actions have been explained on the ability of the Mn-Salen to remove deleterious superoxide (O2-) and hydrogen peroxide (H2O2).
However, in addition to oxidative stress, cells in models for neurodegenerative diseases may also be subjected to damage from reactive nitrogen oxides (nitrosative stress), resulting from elevated levels of nitric oxide (NO) and sister compounds, including peroxynitrite (ONOO-).
We have been examining the interaction of EUK-8 and EUK-134 with NO and ONOO-.
We find that in the presence of a per-species (H2O2, peroxynitrite, peracetate and persulphate), the Mn-Salen complexes are oxidised to the corresponding oxo-complexes (oxoMn-Salen).
OxoMn-Salen are potent oxidants, and we demonstrate that they can rapidly oxidise NO to nitrogen dioxide (NO2) and also oxidise nitrite (NO2-) to nitrate (NO3-).
Thus, these Mn-Salen have the potential to ameliorate cellular damage caused by both oxidative and nitrosative stresses, by the catalytic breakdown of O2-, H2O2, ONOO- and NO to benign species, O2, H2O, NO2- and NO3-.